Stem Cell leukemia/lymphoma syndrome (SCLL) is the only malignancy consistently caused by activation of the FGFR1 kinase, in this case as a result of variant chromosome translocations leading to its constitutive and ligand independent activation. This syndrome is characterized by an atypical myeloproliferative disorder which frequently progresses to AML. In addition, SCLL patients develop T-cell or B-cell lymphomas. Survival of SCLL patients is < 20% despite chemotherapy and bone marrow transplantation which is likely due to the 'stemness' of the disease. Clearly, novel approaches to the treatment of this disease are required to improve this dismal survival record. We have developed a transduction/transplantation approach in immunocompromized mice that expresses the various fusion kinases in normal human CD34+ cord blood cells ex vivo. Once transplanted the transduced stem cells home to the bone marrow and the disease develops exactly as in human patients. All mice develop an atypical myeloproliferative disorder (AMPD) and, depending on the specific rearrangement involved, may also develop T-cell or B-cell lymphoma. In all cases, the atypical MPD progresses to AML, and so this model provides an opportunity to establish the genetic events that accompany this progression, which has broad implications in the clinical management of MPD/AML, since ~25% of de novo AML (without an antecedent MPD/MDS) also overexpress FGFR1 and so a better understanding of its role in this disease could identify novel targets for treatment and provide the means to predict progression from the relatively benign disease to a far more aggressive AML which will kill the patient. These studies will define specific events that drive progression to AML in human cells. In Specific Aim 1, therefore, we will use RNASeq and Exome sequencing to define the genetic events that accompany the progression of AMPD to AML and verify these changes using cell reagents we have developed. Candidate targets will be used in in vivo therapeutic strategies in the human CD34+ mouse model. Of all of the variant chimeric kinases associated with SCLL, the BCR-FGFR1 fusion gene produces a far more aggressive disease, which is possibly due to a contribution of the BCR kinase domain. Leukemia/lymphomas driven by this fusion gene respond poorly to targeted therapies. In Specific Aim 2, therefore, we will use mutant forms of BCR- FGFR1 and RNASeq approaches to define the genetic events that generate this more aggressive disease. Constitutive, ligand independent activation of FGFR1 kinases implies the inappropriate activation of downstream targets through tyrosine phosphorylation. In Specific Aim 3 and we will use a phosphoproteomics approach to identify specific targets of the chimeric FGFR1 kinases and evaluate whether preventing their activation will suppress leukemogenesis.